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Gene Therapy for Neuroblastoma Treatment
Neuroblastoma is a tumor affecting young children (under age 5). The cause of this solid tumor is still unknown (1). Neuroblastoma was originally described by physician James Homer Wright in 1910 (2). A pathologist at Massachusetts General Hospital, Wright described the circular pattern of cells originating from neural tube tissue, thus coining "neuroblastoma." Figure 1 shows the neuroblastoma "Homer-Wright rosettes". Neuroblastoma tumors originate in most cases in the adrenal gland but can metastasize, affecting other places in the body such as bone marrow, eyes, and spinal column (3). Figure 2 shows the areas of the body where metastasis can occur. Patients with neuroblastoma are grouped into 3 categories with 4 stages. The risk categories are low, intermediate and high based on the risk of the child to survive treatment and make a full recovery. Survival rates have been steadily increasing since the first cases of neuroblastoma in 1910. Five-year survival rates for low and intermediate risk groups are now between 75 and 80%. Treatment options range from surgery to chemotherapy as well as immunotherapy and gene therapy for the high risk patients. Figure 3 summarizes the staging and treatment options as well as biomarkers found in the literature (Genetic Marker References 7-15). Strong susceptibility genes includeMYCN , a proto-oncogene associated with tumor growth and ALK , also associated with oncogenesis if amplification of this gene is found. In addition to the summary in Figure 3, gene therapy targets are being identified for treatment. These therapies are for high risk patients where the 5-year survival rate is barely above 50% (1). Gene Therapy Treatment: Adeno-Viral Delivery of IL-24 Adeno-viral gene therapy is a way to deliver targeted genes to specific sites to fight an infection or cancerous tumor cells. In a promising gene therapy technique, Zhuo et al (4) deliver interleukin-24 to SH-SY5Y human neuroblastoma cells. IL-24 has been shown to inhibit tumor growth by inducing apoptosis (4). Thus, delivery of IL-24 to a solid tumor like neuroblastoma could reverse tumor growth. Zhuo et al created two adenovirus delivery vectors by cloning in the IL-24 or GFP control gene into the multiple cloning site of the pTRACK-CMV shuttle plasmid. The plasmids were then transfected into gag and pol expressing HEK293 cells to package virions. Supernatants containing virions were subsequently collected and transduced onto SY5Y cells. Administration of the Ad-IL-24 virion reduced tumor growth by inducing apoptosis in vitro. More promising however is the in vivo data shown by this group. Neuroblastoma cells were injected into mice and tumors allowed to form. When tumors reached 120mm, the tumors were injected with the Ad-IL-24 treatment. Results, summarized in Figure 3, show reduced tumor size, tumor volume, tumor cell pathology, and increased apoptosis when the tumors as compared to the Ad-GFP and PBS control groups. These data suggest a role for adeno-virus delivered IL-24 on treatment of neuroblastoma. In order to determine potential side effects and unwanted consequences more research of this therapy will need to be done in other species besides mice before moving to clinical trials. Gene Therapy Treatment 2: Bone-Marrow Chimera: GRAIN A second gene therapy treatment currently in clinical trials is called GRAIN: "AUTOLOGOUS ACTIVATED T-CELLS TRANSDUCED WITH A 3rd GENERATION GD-2 CHIMERIC ANTIGEN RECEPTOR AND iCASPASE9 SAFETY SWITCH ADMINISTERED TO PATIENTS WITH RELAPSED OR REFRACTORY NEUROBLASTOMA (GRAIN)" (5). This trial is a treatment in which a chimeric antigen receptor specific for neuroblastoma cells is engineering onto T cells. This in effect creates T cells that target the cancer cells, killing them and potentially reducing tumor size. GD2 is a protein found on most neuroblastoma cells (6) with previous reports of Anti-GD2 immunotherapy having favorable treatment outcomes. The problem with the treatment comes in that the engineered T cells do not live long. Therefore, the cells are engineered with not only GD-2, but CD28 , a T cell activation molecule, and OX40 , a receptor that prevents T cells from dying. Additionally, and as a safety precaution for unwanted side effects, the cells are engineered with iCaspase 9 that can be turned on with a medication, triggering death of the newly infused T cells. Caspase 9 is an initiator caspase in the apoptotic cell death pathway. The trials is a collaboration between Baylor College of Medicine (Center for Cell and Gene Therapy), Texas Children's Hospital, the EVAN Foundation, and the National Institutes of Health. Recruitment for the trial began in August 2013 and is expected to finish in August of 2015. Study participants will be followed for efficacy and relapse epidsodes until 2030. The inclusion of a safety switch in this therapy draws attention to the potential problem that the T cells could attack self T cells. If this were the case, the infusion GD-2 T cells can be destroyed without causing problems for the patients. References 1. PubMed Health. "Neuroblastoma." National Institutes of Health. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002381/ 2. Wright JH (1910) "Neurocytoma or Neuroblastoma, a Kind of Tumor Not Generally Recognized." J Exp Med 12: 556-561. PMID: 19867342 3. Maris JM (2010) "Recent advances in neuroblastoma". N Engl J Med 362: 2202-2211. PMID: 20558371 4. Zhuo et al (2013) "Adenovirus arming human IL-24 inhibits neuroblastoma cell proliferation in vitro and xenograft tumor growth in vivo." Tumour Biology. 34(4): 2419-26 PMID: 23609032 5. United States National Insitutes of Health Clinical Trials. "3rd Generation GD-2 Chimeric Antigen Receptor and iCaspase Suicide Safety Switch, Neuroblastoma, GRAIN." 2013. http://clinicaltrials.gov/show/NCT01822652 6. Yang, RK and Sondel, PM. (2010) "Anti-GD2 Strategy in the Treatment of Neuroblastoma." Drugs Future 35(8):665 PMID: 21037966 Additional References: Genetic Marker and GWAS references for neuroblastoma treatment 7. Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, et al. (2008) Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455: 930-935. 8. Maris JM, Mosse YP, Bradfield JP, Hou C, Monni S, et al. (2008) Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med 358: 2585-2593. 9. Diskin SJ, Hou C, Glessner JT, Attiyeh EF, Laudenslager M, et al. (2009) Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459: 987-991. 10. Capasso M, Devoto M, Hou C, Asgharzadeh S, Glessner JT, et al. (2009) Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat Genet 41: 718-723. 11. Wang K, Diskin SJ, Zhang H, Attiyeh EF, Winter C, et al. (2011) Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature 469: 216-220. 12. Nguyen le B, Diskin SJ, Capasso M, Wang K, Diamond MA, et al. (2011) Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci. PLoS Genet 7: e1002026. 13. Cheung NK, Zhang J, Lu C, Parker M, Bahrami A, et al. (2012) Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 307: 1062-1071. 14. Matthay KK, George RE, Yu AL (2012) Promising therapeutic targets in neuroblastoma. Clin Cancer Res 18: 2740-2753. 15. Zhu S, Lee JS, Guo F, Shin J, Perez-Atayde AR, et al. (2012) Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell 21: 362-373.